Endometrial carcinoma (EC), the most common of the gynecological malignancies, has 39,000 new cases and 6,500 deaths yearly. Premalignancy (atypical hyperplasia) is poorly understood, and risk of recurrence and death is currently only stratafiable by grade and stage parameters.
Preliminary treatment for EC is surgical excision. However, recurrence is significant, and chemotherapeutic management is only beneficial in a subset of individuals. Thus, like most cancers, there is a need not only for new modalities of treatment, but also for better identification of the premalignant state, which may provide better opportunities for early intervention and novel treatment modalities.
Reported clinical experiences have established that the histopathologic finding of atypical endometrial hyperplasia identifies individuals at elevated risk for subsequent EC risk. However, such findings are not biddy predictive, indicating heterogeneity in this population with regard to malignant potential (e.g., a Pap test is helpful but undependable, since 30-40% of smears yield false-negative results).
Epithelial Membrane Protein 2 (EMP2), which is expressed in the endometrium, is a four transmembrane protein which plays a critical role in selective receptor trafficking of a variety of proteins and glycolipids, effecting transfer from the post-Golgi endosomal compartment to the plasma membrane, including the transfer of molecules important in growth control, invasion, and metastasis. Accordingly, modulation of EMP2 expression and localization causes pleiotropic changes in the plasma membrane of selected members of several classes of molecules, including integrins, MHC class I and other immunoglobulin superfamily members (e.g., CD54), and GPI-linked proteins. Moreover, EMP2 mediates trafficking of these molecules to glycolipid-enriched lipid raft microdomains (GEMS). GEMs are cholesterol rich microdomains on the plasma membrane, and are associated with the sorting of proteins from the Golgi complex to the plasma membrane. At the plasma membrane, GEMs are thought to be important for receptor complexing and resultant signal transduction. It is possible that cells which utilize distinct GEMSs may permit separate assembly and regulation of distinct subsets of receptosomes.
With such profound consequences, disorders of EMP2 regulation may be a mode of pathogenesis, where alterations in physiologic regulation of EMP2 compartmentalization leads to neoplastic transformation.